Triggers, Facilitators, and Aggravators: Redefining Parkinson’s disease Pathogenesis
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Authors propose a new conceptual model for PD pathogenesis, in which disease-associated factors are divided into three categories: triggers, facilitators, and aggravators.
Triggers are agents or events that begin the disease process; these factors are necessary but insufficient for PD to develop.
Facilitators are factors that allow the disease to spread to, and significantly impact, the central nervous system.
Aggravators directly promote the neurodegenerative process and often have a snowballing effect that exacerbates pathology and spreads the disease beyond the basal ganglia.
Authors propose that clinical therapies aimed at slowing or arresting PD progression should not only be given to patients enriched for the appropriate target (i.e., administered to the appropriate subpopulation), but also be applied during the appropriate temporal phase at which the relevant factor is most active.
Ultimately, combination therapies addressing multiple targets.
Schematic of the ‘triggers, facilitators and aggravators’ conceptual framework for redefining PD pathogenesis.
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Authors define facilitators as factors that help triggers access the nervous system or spread the pathology to more central parts of the nervous system. Authors propose that the facilitator role in disease pathogenesis takes place concomitantly with the triggering event, or after it, usually during the prodromal or asymptomatic phase of PD.
a. Systemic inflammation
Inflammation in PD is present both in the periphery (systemic inflammation) and in the central nervous system
Notably, colon biopsies from PD patient’s exhibit increased mRNA levels for pro-inflammatory cytokines and glial markers, indicative of enteric inflammation. Furthermore, patients with inflammatory bowel disease have a higher incidence of PD, which is substantially reduced by early exposure to anti-inflammatory anti-tumor necrosis factor therapy
In addition, there is an increased risk for PD among people who develop type 2 diabetes, especially at younger ages
b. Mitochondrial dysfunction
Strong evidence from preclinical and clinical studies supports a role for mitochondrial dysfunction in PD pathogenesis.
c. Genetic facilitators
Inherited PD accounts for only 5–10% of all cases, with mutations in at least 15 genes identified as causes of relatively rare monogenic forms of the disease.
Authors define aggravators as factors that directly contribute to the progression of existing symptoms and the onset of late-stage symptoms such as cognitive decline and falls. Aggravators tend to come into play when PD has already manifested clinically, and might affect the rate of progression, accelerating neuronal dysfunction and/or furthering the spread of α-synuclein pathology.
a. Impaired autophagy
Autophagy is the main cellular mechanism employed for disposal of misfolded proteins, damaged organelles, and abnormal or dysfunctional cellular components. Genome-wide studies in PD have identified several polymorphisms that are adjacent to genes involved in lysosomal function and autophagy
b. Neuroinflammation
Neuroinflammation has been closely linked with neurodegenerative diseases and is often characterized by the activation of glial cells and the overexpression of pro-inflammatory mediators.
Additionally, neuroinflammation is a predictive indicator in the development of non-motor symptoms and cognitive decline, further illuminating its role as an aggravator and potential therapeutic target.
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